Chronic right heart failure, like left ventricular failure, is often defined as a syndrome [9] and graded as “risk of developing RVF, asymptomatic RV dysfunction, symptomatic RVF and end-stage RVF” [9]. The 2009 ACCF/AHA Heart Failure guidelines emphasize “that heart failure is not equivalent to cardiomyopathy or cardiac dysfunction.” Instead, heart failure is defined as a clinical syndrome that is characterized by specific symptoms (dyspnea and fatigue) and signs (edema, gallop rhythm, rales) on physical examination. “Heart failure is a symptomatic disorder and is not diagnosed by a single test” and “the mechanisms responsible for the exercise intolerance of patients with chronic heart failure have not been defined clearly” [9]. While it is not difficult to recognize the signs and symptoms of severe RVF, it remains difficult to define RV dysfunction and to predict when an individual patient transits from compensated to decompensated RVF. Clinicians are discussing whether there are different RV phenotypes [10, 11] and whether there are variables that can be measured to determine whether patients have a “failure prone” or a “failure resistant” RV. The flow diagram (Fig. 13.1) proposes that neurohormonal overdrive as well as inadequate RV hypertrophy may lead to RVF. We believe that RV dysfunction exists when the patient’s dyspnea can be explained hemodynamically by an elevation of the right atrial pressure and/or a lower than normal cardiac index at rest. Perhaps the condition of “at risk of developing RVF” describes the asymptomatic patients which demonstrate mild abnormalities when examined by echocardiography (see Chap. 10) or cardiac MRI (see Chap. 12). We wonder whether a mildly elevated BNP level in patients with PAH may be a reliable marker of early RVF, however, it may be wishful to think that BNP alone will be able to explain and predict RV dysfunction in each individual case, and if so, this finding would violate the “no single diagnostic test” rule.

In patients with pulmonary hypertension, the increase in pulmonary vascular resistance impacts the RV. Analogous to chronic obstructive pulmonary diseases (COPD), which are defined by an increased resistance to airflow, the right ventricle is challenged when working against an increased resistance to blood flow. The increase in resistance can be in close proximity to the RV outflow tract as in the setting of pulmonary artery stenosis or central pulmonary artery blood clots and modeled by main pulmonary artery banding (PAB), however, in patients with PAH the structural changes occur in nearly all of the small pulmonary arteries, accounting for the resistance that the RV pumps against. A second component that changes the response of the RV to increased blood flow resistance is the quality or behavior of the Windkessel of the large central pulmonary vessels [12]. Briefly, the arterial side of the lung circulation consists of the central, large capacitance vessels and the small precapillary resistance vessels. The capacitance vessels or conduit arteries can expand and decrease the flow wave energy that is transmitted to the resistance vessels and capillaries. In pulmonary hypertension the conduit arteries become stiff and less compliant. As the pressure within the RV cavity rises, so does the RV wall stress. Wall stress is inversely proportional to wall thickness. A robustly muscular RV, as in patients with Eisenmenger physiology, experiences less severe wall stress than a less muscularized “stretched” RV. Increased wall stress will also compromise the perfusion of the RV muscle. The schematic below (Fig. 13.1) integrates these various failure components. This schematic entails two causality concepts that are still hypothetical: (1) that RV stress and strain lead to neurohormonal activation and (2) that factors which we designate as “intrinsic to the myocardium” are of pathogenetic importance, and thus contribute to RV failure development and/or progression.

It has been recognized for some time that the RV of patients with Eisenmenger physiology does not easily fail. Again, hypothetically, the “Eisenmenger RV” is as muscular as the LV and is characterized by a generous vessel supply. H.A. Zimmerman, more than half a century ago, performing postmortem coronary angiography, demonstrated an increase in the number of small coronary branches in the right and left ventricle, “so much so in the right ventricle as to approach in number the ramifications of the left ventricle” (Fig. 13.2) [13]. We conclude that a robustly muscular and well-vascularized RV is not ischemic and subject to less wall stress. RV hypertrophy per se appears, indeed, not to correlate with mortality [14]. However, in PAH patients blood flow per gram of RV hypertrophy and the mean systolic/diastolic flow ratio in the right coronary artery decline with rising RV systolic pressure [15] and with increasing RV mass (Fig. 13.3). In addition, right and left ventricular myocardial perfusion reserves correlate with right ventricular function [16]. Thus the RV in severe PAH is likely ischemic, but the “Eisenmenger RV” is not. As there is a strong inverse correlation between the RVSP and mean right coronary artery blood flow, stretch/strain of the RV may be an important component limiting coronary perfusion. Quaife et al. estimated the relative RV wall stress in idiopathic PAH patients and found that significant RV hypertrophy tended to lower the RV wall stress. Neither RV end-diastolic volume nor cardiac output correlated with RV wall stress [17] (Fig. 13.4). High plasma levels of ANP and BNP may be signals which emanate from a stretched right atrium and ventricle—relatively independent of the cardiac output. Indeed Sachdev et al. reported that high RV free wall strain was associated with higher BNP levels [18] (Fig. 13.5).

Hypokinesis, dyskinesis, failure of the right ventricle to empty during systole, bowing of the interventricular septum, and underfilling of the left ventricle are all described in great detail in previous chapters. These changes are to varying degrees due to regional abnormalities, hypertrophy, fibrosis, or dilatation and may also be related to the different shape of the RV and the underling myoarchitecture and fiber architecture of the RV [19, 20]. Most of the studies that investigated the relationship between cardiac architecture and ventricular function have so far focused on the left ventricle [22, 23] (see also Chap. 17).

Cardiac autophagy can be a maladaptive response to chronic hemodynamic stress [58–61] and one hallmark of myocardial hibernation [62–64]. The right ventricle, stressed by a chronically elevated afterload, undergoes hypertrophy which is required for successful adaptation to the chronic stress and strain. As stated, mechanisms which govern the transition from hypertrophy to RV failure are still poorly understood; however, the regulation of protein turnover—synthesis and proteolysis during the transition phase—is critically important. During hypertrophic growth, enhanced protein synthesis leads to an increase in the individual size of the myocardiocytes, whereas decompensation is associated with proteolysis, a switch from cell growth to cell death and replacement fibrosis. Our published data confirm this concept: the hypertrophic RV after chronic pulmonary artery banding is characterized by an increase in the size of the myocardiocytes, a cell growth-directed gene expression pattern and a maintained capillary network [65]. In contrast, in the failing RV the gene expression pattern (RV failure gene expression program) is characterized by a depressed cell growth pattern [27], and tissue analysis reveals increased proteolysis and increased apoptosis. Damaged proteins and organelles, if not eliminated from the cells via autophagy, accumulate and become toxic (proteotoxicity [66]) or trigger apoptotic death [67]. Zhu et al. showed in 2007 that in the setting of left ventricular pressure overload cardiac autophagy is maladaptive and contributes to heart failure progression [58]. The authors also demonstrated increased expression of Beclin 1 levels in pressure-overloaded LV tissues and concluded that Beclin 1 promotes autophagy and LV failure [58]. Importantly and in contrast, autophagy is necessary for the hypertrophic adaptive response of the heart [59]. Because RV hypertrophy is necessary for the successful adaptation of the RV to chronic pressure afterload, inhibition of autophagy during the development of hypertrophy may be detrimental, but inhibition may be beneficial when autophagy has become maladaptive and contributes to heart failure progression. Figure 13.7 is an attempt to construct a mechanistic sequence of events which begins with cardiac stress and has as an end point apoptotic cell death or alternatively a return to cellular homeostasis via organelle and protein clearance, which counterbalances the congestion of the cells with damaged proteins and membrane fragments.

Thus, a fundamentally important question is whether in heart diseases autophagy is helpful or harmful. Once the cardiac stress has been initiated, the cells, in order to become not congested or overloaded with toxic proteins, depend on autophagy. Whereas homeostatic during the phase of adaptive hypertrophy, autophagy can become counterproductive leading to the so-called Type II programmed cell death [68, 69]. Whether autophagy is increased in the failing RV of patients with severe PAH or impaired is unknown, but can be presumed. If we can extrapolate from left heart failure (see above), then we would expect maladaptive autophagy in RVF as a component which contributes to RVF progression.

As mentioned, myocardial tissue hibernation is one of the conceptual models of progressive heart failure, which, for a lack of a better explanation, should be used to also explain progressive RVF. Global myocardial ischemia may be a consequence of microvascular dysfunction (see below). Indeed, May et al. generated myocardial hibernation in mice by conditional impairment of VEGF signaling [63]; in this model autophagy activity was increased in association with capillary loss. Once the conditional VEGF inhibition was reversed, hibernation was reversed as the capillary network was restored. These studies are of great interest, specifically because they indicate that microvascular dysfunction, autophagy, and hibernation are potentially reversible. Subsequently this group of investigators applied proteomic analyses and found, in addition to protein expression changes, that hibernation was characterized by a reduced state of phosphorylation of the myosin light chain 2 and of cardiac troponin I, while the abundance of these proteins was unchanged [70]. Unlike myocardial infarction, the hibernating myocardium does not undergo cell death, but can be salvaged; the mechanisms whereby hibernating myocardium survives remain to be elucidated [64]. It is conceivable that mechanisms which control type II programmed cell death play a critical role.

Loss of myocardial capillaries is one component of heart microvascular dysfunction. Injury and loss of integrity of remaining capillary endothelial cells is an additional component. Cardiac capillary endothelial cell damage can be demonstrated by electron microscopy (Fig. 13.8) and function defects are reflected in the altered pattern of protein expression that can be shown by immunohistochemistry. As shown and discussed above, VEGF and intact signaling via its receptors is essential for cardiac capillary endothelial cell maintenance [63]. VEGF gene expression is controlled by the transcription factors HIF-1α and PGC-1α. PGC-1α is preferentially expressed in tissues with high energy metabolism; there this transcription factor coordinates genes involved in cellular uptake and mitochondrial metabolism of fatty acids as well as mitochondrial biogenesis. Gomez-Arroyo et al. recently reported a decreased expression in the failing, RV but not in the stressed RV, that responded with adaptive hypertrophy after pulmonary artery banding (PAB) [71]. The altered expression of genes of the PPAR signaling pathways had been first discovered as a result of the microarray gene expression screening analysis of failing RV tissues [27]. Interestingly, HIF-1α expression is not decreased in the failing RV [72], however, the expression of FHL2 (four and a half LIM domains 2) was increased in the failing RV [73], a finding also reported by Mayr et al. [70] in the hibernating myocardium. FHL2 directly interacts with HIF-1α to repress an HIF-1α-dependent transactivation of its target genes. Taken together, one mechanism of capillary rarefaction in the failing RV is a decrease of HIF-1α and PGC-1α-dependent expression of the angiogenic maintenance factor VEGFA. The upstream mechanisms which regulate PGC-1α gene and protein expression in the setting of RVF are still unexplored. We wonder whether the global RV loss of microvessels can be additionally explained by circulating proapoptotic factors such as cytokines or microRNA-containing endothelial cell microparticles [70].

One important question to address is whether RV hypertrophy per se is sufficient to cause RV ischemia. As will be discussed in Chap. 9, acute occlusion of the right coronary artery, even for a short time, decreases the RV contractile force [74], thus the relationship between RV ischemia and RV contractility is understood and the question whether the hypertrophic RV is ischemic is important. In contrast to the left ventricle, a pressure overload of the RV results in a selective increase in the resting transmural blood flow per gram of hypertrophied RV [75] at least in dogs. Again, in dogs, it has been shown that there is right coronary vasodilation during systemic hypoxia which is to a large extent explained by nitric oxide [76]. Huo et al. [77] analyzed the coronary arterial tree in RV hypertrophy and concluded that RV hypertrophy functionally restores the perfusion at the arteriolar and capillary level. These data agree with older measurements of cross-sectional capillary density and numerical capillary density in RV hypertrophy [78].

We postulate that apoptosis occurs during the transition from compensated RVH to RV failure and that maladaptive autophagy and capillary loss in the RV contribute to the progression of the RV failure. In this scenario it makes sense to explore therapeutic strategies that would decrease heart cell apoptosis. Beta-adrenergic receptor (BAR) blockers have been used for many years to treat patients with left-sided heart failure and they are highly effective in reducing the morbidity and mortality associated with heart failure [79]. Long-term BAR blockade causes left-ventricular volumes and LVEF to return to normal (reverse remodeling). BAR blockers improve LV remodeling and the mechanisms of this effect may include protecting the myocardiocytes against the toxic effects of catecholamines and reversing the cellular metabolic remodeling [28, 80, 81]. Alternatively BAR blockers, by decreasing heart rate could make the pump work more economical and improve the oxygen supply/demand ratio. Although a number of different BAR blockers have been used, improved outcomes appear to be more frequent when the BAR blocker carvedilol had been used [79], and the authors of the randomized placebo-controlled CHRISTMAS trial tested the hypothesis that carvedilol might improve the function of hibernating myocardium [82]. For more details on carvedilol and RV failure, see Chap. 19.